Dr. Martin Dietrich discusses the use of HER2-targeted antibody-drug conjugates (ADCs) in gastrointestinal (GI) cancers, particularly focusing on upper GI tumors, gastric cancer, and colorectal cancer.

Dr. Dietrich begins by noting the concerning features of upper GI tumors, especially their poor chemosensitivity. While data with trastuzumab emtansine (T-DM1) in cholangiocarcinomas and pancreatic carcinomas was disappointing, the DESTINY-Gastric01 study showed positive results in HER2-positive gastric and gastroesophageal junction tumors that had received two prior lines of chemotherapy. However, a higher dose was required to establish efficacy, leading to increased toxicity and lower overall response rates.

The treatment landscape for gastric cancer has shifted, with immunotherapy moving to the first-line setting in combination with trastuzumab for HER2-amplified and PD-L1-positive disease. Treating gastric and gastroesophageal junction patients can be challenging due to factors such as malnutrition and poor tolerance.

In colorectal cancer, the DESTINY-CRC01 study demonstrated promising results for trastuzumab deruxtecan (T-DXd) in HER2-amplified, unresectable disease. Response rates were close to 50%, better than those seen in upper GI cancers. Dr. Dietrich considers T-DXd as a second-line HER2-targeted option for colorectal cancer, although tyrosine kinase inhibitors (TKIs) currently have slightly higher response rates and better safety profiles.

ADCs have the ability to overcome intrinsic resistance mutations in GI cancers, a feature also seen in breast cancer. However, the higher dosing required can be challenging in clinical practice, and intrinsic resistance mutations to these treatments can also occur.

Summary generated by Claude AI.